The present invention relates to irradiation systems, generally and, more particularly, but not by way of limitation, to methods and means of variably attenuating radiation.
When radionuclides are administered for diagnostic purposes in nuclear medicine, the absorbed doses received by the critical organs and tissues of the target are usually sufficiently low that the biological effects cannot be measured with any reliability. In these instances, reliance solely on calculated absorbed doses may be appropriate and sufficient for risk estimations and comparison of the relative merits of different radiopharmaceuticals. However, when radionuclides are administered for therapeutic purposes, or in cases involving accidental ingestion of high levels of radioactivity, dependence on untested absorbed dose calculations can lead to serious errors in predicting the biological consequence of the radiation exposure. Such concerns are particularly relevant to complex biological systems, such as the bone marrow. For example, computational bone marrow dosimetry techniques used in radioimmunotherapy have failed to yield a reasonable correlation between absorbed dose and biological response of the marrow. The shortcomings and failures of existing techniques may include, among others, the following reasons: the underlying assumptions in the absorbed dose calculations; differences in dose rate patterns; prior treatment history and bone marrow reserve; and nonuniform activity distributions in the marrow compartment. These problems are not unique to bone marrow, but can also exist for other organs and tissue as well. Hence, in view of the limitations inherent in computational dosimetry, a need exists for reliable biological dosimeters to verify the computational methods.
It is well known that the biological effect of a given radiation insult is highly dependent on factors such as total absorbed dose, dose rate, linear energy transfer (LET) of the radiations, and radiosensitivity of the tissue. See: ICRP, RBE for Deterministic Effects, Publication 58, International Commission on Radiological Protection, Pergamon, Oxford (1989); and ICRP, 1990 Recommendations, Publication 60, International Commission on Radiological Protections, Pergamon, Oxford (1991); both of which are incorporated by reference herein in their entirety. While the consequences of these variables are well established for acute and constant chronic radiation exposure conditions, little is known about the role of these variables for exposures involving internal radionuclides. Also see: Testa, et al., Biomedicine, 19:183-186 (1973); Wu, et al., Int. J. Radiat. Biol., 27:41-50 (1975); and Thames, et al., Br. J. Cancer, 49, Suppl. VI:263-269 (1984); all of which are incorporated by reference herein in their entirety.
Internal radionuclides are unique in that they deliver radiation exposures at dose rates that vary exponentially in time as determined by the effective half-time, which in turn is dictated by the physical half-life of the radionuclide and the biological half-time of the radiochemical. Further complications to the dose rate pattern can emerge when the uptake of the radiochemical by the tissue is slow, followed by a complex multicomponent exponential clearance pattern. Although the total dose delivered to a tissue may be the same, differences in dose rate patterns from one radiochemical to another can have a major impact on the biological response of the tissue. See: Fowler, Int. J Radiat. Oncol. Biol. Phys., 18:1261-1269 (1990); Langmuir, et al., Med. Phys., 20, Pt. 2:601-610 (1993); Rao, et al., J. Nucl. Med., 34:1801-1810 (1993); and Howell, et al., J. Nucl. Med., 35:1861-1869 (1994); all of which are incorporated by reference herein in their entirety. Such differences cannot always be predicted a priori using computational absorbed dose estimates and extrapolations based on the response to acute and chronic exposure at constant dose rates. Therefore it is imperative to develop experimental irradiators that are capable of precisely delivering exposure that simulate the conditions encountered with internal radionuclides and to establish biological endpoints that can serve as "dosimeters" so that the consequence of different dose rate patterns on the biological effect can be investigated.
Two endpoints which may serve as biological dosimeters are survival of bone marrow granulocyte-macrophage colony-forming cells (GM-CFC) and induction of micronuclei in peripheral blood reticulocytes. See: Testa, Cell Clones: Manual of Mammalian Cell Techniques, Edinburgh: Churchill-Livingstone, 27-43 (1985); and Lenarczyk, et al., Mutation Res., 335:229-234 (1995); both of which are incorporated by reference herein in their entirety.